The lesions of atherosclerosis represent a series of highly specific cellular and molecular responses that can be viewed as an inflammatory disease process. Experimental, pathologic, and clinical observations support a critical role for macrophages in atherogenesis. Using a homology screening strategy we identified KLF4 expression in human macrophages and found it is markedly induced in response to proinflammatory cytokines (IFN-gamma, TNF-alpha, IPS) and decreased by the anti-inflammatory growth factor, transforming growth factor (TGF)-betal. Overexpression of KLF4 in macrophage cell lines potently induces macrophage activation markers (iNOS, CD11b, MMP-12, and MCP-1). In contrast, KLF4 potently inhibits anti- inflammatory gene responses mediated by TGF-beta1 and SmadS. Furthermore, studies to date suggest that KLF4 is able to form a cooperative interaction with the NF-kB family member, p65, a critical regulator for inflammation. The studies in this proposal will (1) define the molecular basis for KLF4's ability to induce iNOS and inhibit TGF-beta1 signaling in macrophages and (2) assess the role of KLF4 on macrophage effector function and atherosclerosis in vivo. [unreadable] [unreadable] [unreadable]